Considerable progress has been made over the last decade towards understanding host factors that contribute to differential susceptibility to HIV-1 transmission and AIDS progression. Genetic background has been shown to be an important determinant of both HIV-1 infection and AIDS progression. However, little work has been directed to understanding the role(s) of polymorphisms in innate immunity genes in HIV transmission or AIDS progression. Toll-like receptor 4 (TLR4), which mediates responses to Gram-negative bacteria (e.g. lipopolysaccharide or endotoxin) in mouse and humans, has also been implicated as a determinant of HIV infection and viral replication in vitro. Recently, two functional polymorphisms in human TLR4 have been reported: 896 A to G (Asp299Gly) and 1190 A to G (Thr399Ile). Both loss of function mutations have been demonstrated to have functional relevance to human response to endotoxin. To evaluate the potential role of TLR4 in HIV-1 transmission and AIDS progression we established a research collaboration with the multicenter AIDS cohort study (MACS), which is funded by NIAID. We designed the study to test the following hypotheses in homosexual men recruited to MACS: 1) the Asp299Gly and Thr399Ile polymorphisms in TLR4 confers enhanced risk to HIV-1 transmission, and 2) the TLR4 polymorphisms are associated with slowed progression to AIDS in HIV-infected individuals. [unreadable] [unreadable] A second project has been designed to investigate the mechanisms of susceptibility to respiratory syncytial virus (RSV) infection and disease progression. RSV is the leading viral respiratory cause of hospitalization in infants and young children in the United States and in the world. The reason why some previously healthy infants develop LRI (bronchiolitis and pneumonia) while others remain asymptomatic or only develop upper respiratory tract symptoms after RSV infection is not well understood. Evidence exists that the degree of previous injury of the lung parenchyma in small infants could play a role in disease severity, as children with chronic lung disease are at high risk of RSV LRI. However, the majority of hospitalizations occur in previously healthy infants. Another potentially important factor that can cause lung injury during RSV LRI is innate immunity. The pulmonary infiltration during RSV LRI is composed overwhelmingly by neutrophils and macrophages and damage to the small airways (10-300 microns) affected by the virus could easily cause debris accumulation in the lumen, inflammation and edema of the small airways, and compromise ventilation. Further, most infants with RSV-associated wheezing do not respond to b2-bronchodilators, but may benefit from inhaled a-agonists that decrease edema/inflammation. Additionally, high levels of CXC chemokines (particularly MIP-1a, MCP-1 and IL-8) have been associated with increased RSV disease severity.